Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice.

Abstract

High density lipoprotein (HDL) is the major plasma lipoprotein found in mice fed normal laboratory chow containing 4% fat. When female mice from some inbred strains, such as C57BL/6, are fed a high fat diet (1.25% cholesterol, 15% fat, and 0.5% cholic acid), the levels of HDL-cholesterol decrease by about 50%, and lipid staining lesions form in the aorta within 14 weeks. In other strains of mice, such as C3H and BALB/c, HDL-lipid levels decrease only slightly, and few or no aortic lesions are observed at 14 weeks.

The emergence of mouse models of atherosclerosis and their relevance to clinical research

“…In 1987, the first mouse diet-induced atherosclerosis susceptibility gene locus, called Ath-1, was mapped using recombinant inbred (RI) strains made from the susceptible C57BL/6 strain and either the resistant C3H or BALB/c strains [20]. RI strains are derived from the F1 progeny of two inbred strains by successive generations of vertical brother/sister matings, so that each RI strain is homozygous at all genetic loci, but each locus may be derived from either parental strain.…”

“…By comparing a number of RI strains (each of which has been mapped using polymorphic markers so that the parental origin is known at many intervals along the genetic map of each chromosome) it is possible to find linkage between a phenotype (disease susceptibility) and the inheritance of a particular parental genetic locus. The Ath-1 locus was mapped to chromosome 1, near but separable from the apoAII gene, and was associated with both diet-induced atherosclerosis susceptibility and decreases in HDL levels [20][21][22][23]. The Ath-1 locus was reported to control HDL levels via regulation of HDL catabolism [24].…”

“…The Ath-1 locus was reported to control HDL levels via regulation of HDL catabolism [24]. A similar method, using RI strains made from the atherosclerosis-susceptible and resistant strains C57BL/6 and A/J, respectively, was used to define an additional genetic component, Ath-2, for which the atherosclerosis-resistant allele acts dominantly, although the map location was not defined [25]. The Ath-3 locus on chromosome 7 was defined similarly using RI strains also made from C57BL/6 and A/J strains [26].…”

Using Mice to Dissect Genetic Factors in Atherosclerosis

“…These studies suggested that lesions were controlled by a small number of major genes, designated Ath1, Ath2, and Ath3. 12,[22][23][24] Subsequent studies indicated a more complex picture. [25][26][27][28][29] As discussed later, the HDL component of the Ath1 phenotype proved to be caused by polymorphisms of apoA-II.…”

“…8 In the early 1980s, several groups characterized lipoproteins in mice and demonstrated significant genetic variations in lipoprotein levels and structures among inbred strains. 9,10 In the mid1980s, Paigen and colleagues (Paigen et al, 11,12 Nishima et al 13 ) modified the original Thompson diet and refined the methods for evaluation of aortic lesions. In the early 1990s, transgenic technologies led to the development of mouse models that can develop large, advanced lesions, in contrast to the fatty streak lesions observed after feeding of the atherogenic diets to wild-type mice (reviewed in Breslow 14 ).…”